Fw: Toxicity, Heavy Metals

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Toxicity, Heavy Metals Last Updated: May 25, 2001 Author: J Ferner, MD, Instructor, Department of Emergency Medicine, Saint Mercy Medical Center Editor(s): Mark Louden, MD, FAAEM, Consulting Staff, Department of Emergency Medicine, Saint Francis Medical Center; T VanDeVoort, PharmD, DABAT, Manager, Clinical Assistant Professor, Pharmacy Department, Regions Hospital; Benitez, MD, MPH, FACMT, Associate Professor, Departments of Emergency, Pediatrics and Environmen, University of Rochester Medical Center; Managing Director, Associate Medical Director, Finger Lakes Regional Poison and Drug Information Center; Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and J Roberge, MD, MPH, FAAEM, FACMT, Research Director, Department of Emergency Medicine, Ohio Valley Medical Center; Clinical Associate Professor, Department of Emergency Medicine, University of Pittsburgh Background: Heavy metal toxicity represents an uncommon, yet clinically significant, medical condition. If unrecognized or inappropriately treated, heavy metal toxicity can result in significant morbidity and mortality. The most common heavy metals implicated in acute and/or chronic conditions include lead, arsenic, and mercury. Lead is the most significant toxin of the heavy metals. Industrial decisions, such as the addition of lead to paints, dyes, and gasoline, have created an epidemic of lead poisonings. Lead is a naturally occurring substance and can be found in organic and inorganic forms. Inorganic forms of lead typically affect the CNS, peripheral nervous system (PNS), hematopoietic, renal, GI, cardiovascular, and reproductive systems. Organic lead toxicities tend to predominately affect the CNS. The inorganic forms of lead are absorbed through ingestion or inhalation, whereas organic lead salts are absorbed through the skin. Only about 10% of an ingested dose is absorbed in adults, but the absorbed percentage may be much greater in children. Lead absorption is enhanced by deficiencies of iron, calcium, and zinc. Under typical conditions, lead is absorbed and stored in several body compartments. Five to ten percent is found in the blood, most of which is located in erythrocytes; 80-90% is taken up in the bone and stored with the hydroxyapatite crystals, where it easily exchanges with the blood. Some authorities list the half-life of lead in the bone as long as 30 years, while others estimate the lead half-life in bone to be 105 days. Generally, excretion of lead is slow, with an estimated biologic half-life in soft tissues of 24-40 days. The remainder of the stored lead is found in soft tissue, notably the kidney and brain. The primary route of excretion is through feces (80-90%). To a lesser extent, lead is excreted in urine (10%). Lead passes the placental barrier and is found in breast milk. A correlation exists between lead toxicity and fetal wastage, premature rupture of membranes, and sterility. Pathophysiology: The pathophysiology of the heavy metal toxidromes remains relatively constant. Heavy metals bind to sulfhydryl groups in proteins, resulting in alterations of enzymatic activity. Nearly all organ systems are involved in heavy metal toxicity; however, the most commonly involved organ systems include the CNS, PNS, GI, hematopoietic, renal, and cardiovascular (CV). To a lesser extent, lead toxicity involves the musculoskeletal and reproductive systems. The organ systems affected and the severity of the toxicity vary with the particular heavy metal involved, the age of the individual, and the level of toxicity. Frequency: In the US: Of the heavy metals, toxicity by chronic lead exposure is the most commonly encountered. The National Health and Nutrition Examination Survey (NHANES III) conducted from 1988-1990 found that 0.4% of persons aged 1 year and older had blood levels of lead of 25 mcg/dL or higher. The data also noted that, among those aged 1-5 years, an estimated 1.7 million children had blood levels greater than 10 mcg/dL. The syndrome of childhood plumbism caused by the ingestion of lead is believed to affect more than 2 million American preschool-aged children. Lead toxicity has a significantly higher prevalence among the African American population and in lower socioeconomic areas. Reliable figures for the prevalence of mercury and arsenic toxicities are not available. These toxidromes are usually encountered from industrial exposures. Arsenic exposure, however, often occurs outside the industrial realm because of its uses as a rodenticide and a commonly employed homicidal and suicidal agent. Mortality/Morbidity: As previously noted, heavy metal toxicities are relatively uncommon. However, failure to recognize and treat heavy metal toxicities can result in significant morbidity and mortality. Encephalopathy is a leading cause of mortality in patients with heavy metal toxicity. Race: A higher incidence of heavy metal toxicity occurs in the African American population in the US because of delays in removing lead sources from lower socioeconomic areas. Sex: Little or no difference in prevalence exists. Occupations with heavy metal exposure that predominantly involve a particular sex are associated with higher rates of exposure in that sex. Age: Several points are of concern in heavy metal toxicity with respect to age. Generally, children are more susceptible to the toxic effects of the heavy metals and are more prone to accidental exposures. Inorganic lead salts enter the body by way of ingestion or inhalation. For adults only about 10% of the ingested dose is absorbed. In contrast, children may absorb as much as 50% of an ingested dose. The percentage of absorbed lead is increased with deficiencies of iron, calcium, and zinc. Children and infants are prone to developmental delays secondary to lead toxicity. History: The history is the most critical aspect of diagnosing heavy metal toxicity. Most acute presentations involve industrial exposure. A complete history, including occupational, hobby and recreational, and environmental exposure, may be the difference in diagnosing heavy metal toxicity. A history of ingestion often leads to the diagnosis in children. Physical: Physical findings in lead toxicity vary with age and dose. Any combination of GI complaints, neurologic dysfunction, and anemia should prompt a search for lead toxicity. GI complaints predominate in adults. Children are more prone to CNS dysfunction, including encephalopathy. Encephalopathy is rare in adults. Encephalopathy may present as an acute event with seizures, or it may develop slowly over weeks to months with variable nonspecific complaints. Closely examine the patient’s history to elicit evidence of heavy metal exposure. As with lead, arsenic toxicity symptomatology varies with several factors, including concentration, rate of absorption, and the chemical form ingested. GI complaints, predominately diarrhea, are observed in acute arsenic toxicity. Neurologic complaints have been noted in cases of acute arsenic toxicity. Arsenic toxicity is often confused with Guillan-Barré syndrome. Acute renal failure is not uncommon and, when observed, is often fatal. Mercury toxicity often presents with CNS dysfunction (eg, erethism) Chronic exposure may lead to an intention tremor, the most consistent neurological finding in chronic toxicity. Inorganic forms of mercury may cause severe GI complaints (eg, corrosive esophagitis, hematochezia) Acrodynia (ie, Pink disease) is observed in children with mercury toxicity. Physical findings include rash and desquamation of the hands and feet. Gingivitis, stomatitis, and salivation are frequently noted. WORKUP Lab Studies: Lead toxicity Blood lead levels Diagnosis is made with venous blood lead levels in association with symptomatology. Blood lead levels higher than 10 mcg/dL are considered toxic. Complete blood count (CBC) with peripheral smear Findings may include basophilic stippling of the RBCs on peripheral blood smears. Remember that basophilic stippling is not specific for lead toxicity and may be observed in arsenic toxicity, sideroblastic anemia, and thalassemia. The anemia of lead toxicity may be normocytic of microcytic. Mercury toxicity Collect a 24-hour urine specimen for measurement of mercury levels (except in short-chain alkyls). Measure whole blood mercury levels for short-chain alkyls. Arsenic toxicity Collect a 24-hour urine specimen for measurement of arsenic level. Obtain a CBC. Collect hair and fingernail clippings, although this is not as helpful as blood tests, unless environmental contamination of specimens can be ruled out. Imaging Studies: Lead toxicity Long bone x-rays in children may demonstrate the classic lead bands noted most commonly around the knee joint. X-ray evaluation of the knee also may reveal lead bands, which are horizontal metaphyseal lines that represent failure of the bones to remodel, not lead. Lead lines are not observed in adults. Abdominal radiographs may demonstrate the presence of radiopacities, such as paint chips and lead weights (eg, fishing sinkers, curtain weights). Also, the presence of retained bullets, especially if near a joint, is associated with elevated lead levels in many individuals. Arsenic toxicity: Abdominal radiographs occasionally show metallic fragments, which indicate the need for whole bowel irrigation. Mercury toxicity: Chest radiographs may show pneumomediastinum or pneumothorax following elemental mercury exposure or radiodense pulmonary emboli following intravenous mercury injection. TREATMENT Section 6 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Emergency Department Care: Lead toxicity Treatment for acutely ill patients includes whole bowel irrigation with polyethylene glycol electrolyte solution if radiographic evidence of lead toxicity is present. Perform chelation therapy and aggressive hydration. Diagnosing lead toxicity can be difficult; a history of lead exposure is instrumental in the diagnosis process. Anemia, in the presence of neurological and gastrointestinal symptoms, should alert the physician to the possibility of lead toxicity. Consider possibility of lead toxicity in all children presenting with encephalopathy. Arsenic toxicity Correct dysrhythmias and hypotension (significant fluid losses generally occur and require aggressive rehydration). Perform gastric lavage. Perform whole bowel irrigation if radiographic evidence of arsenic toxicity is present. Administer chelation therapy. Mercury toxicity Perform GI decontamination with activated charcoal (without a cathartic). GI decontamination should be withheld if inorganic mercury-associated corrosive effects are present in the GI tract. In such instances, upper endoscopy is indicated to detail the extent of injury and guide subsequent GI therapy. Control diarrhea. Administer chelation therapy. Consultations: As with any intentional ingestion or overdose, place patient in closely a monitored unit and consult a medical toxicologist and psychiatrist. Contact a certified poison control center or medical toxicologist. Consult a gastroenterologist if the possibility of corrosive GI effects is present. MEDICATION Section 7 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Lead toxicity The key to treating lead toxicity is removal of the offending agent and reducing the total body load of lead. Chelation agents (eg, edetate calcium disodium, dimercaprol, DMSA) are used to reduce the body stores of lead. Arsenic toxicity Chelation therapy with BAL, DMSA, or d-penicillamine is the primary treatment of arsenic toxicity. Removal of the offending agent and aggressive gastric decontamination aids in reducing ongoing absorption of arsenic. Hemodialysis may be beneficial in patients with acute renal failure. Mercury toxicity Treatment of mercury toxicity includes removing the insulting agent, gastric decontamination, and chelation therapy with BAL, DMSA, and d-penicillamine. Drug Category: Chelation agents -- These drugs supply sulfhydryl groups for the heavy metals to attach and, subsequently, may be eliminated from the body. Drug Name Dimercaprol (British Anti-ite; BAL) -- DOC in the treatment of lead, arsenic, and mercury toxicity. Administered IM q4h, mixed in a peanut oil base. Chelates intracellular and extracellular lead and is excreted in urine and bile. May be given to patients with renal failure. Adult Dose Lead toxicity: 75 mg/m2 IM q4h for 5 d; not to exceed 24 mg/kg/d IM Arsenic toxicity: 3-5 mg/kg IM q4h for 2 d; followed by 3-5 mg/kg IM q6-12h prn Mercury toxicity: 3-5 mg/kg IM q4h for 2 d; followed by 3-5 mg/kg IM q6h for 2 d; followed by 3-5 mg/kg IM q12h for 7 d Pediatric Dose Lead toxicity: Administer as in adults Arsenic toxicity: If symptomatic without encephalopathy: 50 mg/m2/d IM In asymptomatic children with blood lead >45 mcg/dL: 50 mg/m2/d IM Mercury toxicity: Administer as in adults Contraindications Documented hypersensitivity; concurrent iron supplementation therapy Interactions Toxicity may increase when coadministered with selenium, uranium, iron, or cadmium Pregnancy C - Safety for use during pregnancy has not been established. Precautions May be nephrotoxic and may cause hypertension; caution with oliguria or G-6-PD deficiency; may induce hemolysis in G-6-PD deficiency Drug Name Edetate disodium, EDTA (Chealamide) -- Second-line for lead toxicity. Chelates only extracellular lead and may induce CNS toxicity if BAL therapy not initiated first. Begin therapy 4 h after BAL is given. Only given IV, and continuous infusion is recommended. Not recommended with renal failure. Because of potential for renal toxicity, patient should be well hydrated. To prevent hypocalcemia, use only calcium disodium salt of EDTA for chelation in heavy metal toxicity. Adult Dose Encephalopathic patient: 1500 mg/m2/d as continuous IV infusion Symptomatic nonencephalopathic adult may be treated combined with BAL or alone Pediatric Dose Encephalopathic patient: 1500 mg/m2/d continuous IV infusion Symptomatic non-encephalopathic patient: 1000 mg/m2/d continuous IV infusion Contraindications Documented hypersensitivity; renal failure Interactions Enhances the hypoglycemic effects of insulin in diabetic patients Pregnancy C - Safety for use during pregnancy has not been established. Precautions Patient should be well hydrated; may worsen CNS toxicity if administered before BAL therapy Drug Name Succimer (Chemet) -- Metal chelator, analog of dimercaprol, used in lead poisoning. Particularly useful in children with blood levels of lead >45 mcg/dL. Repeat dosing may be necessary. Adult Dose Lead toxicity: 10 mg/kg PO q8h for 5 d followed by 10 mg/kg PO q12h for 14 d Arsenic toxicity: 10 mg/kg PO q8h for 5 d followed by 10 mg/kg PO q12h for 14 d Pediatric Dose Administer as in adults Contraindications Documented hypersensitivity Interactions Do not administer concomitantly with edetate calcium disodium or penicillamine Pregnancy C - Safety for use during pregnancy has not been established. Precautions Caution in renal or hepatic impairment; to prevent toxicity, patient should be well hydrated Drug Name Penicillamine (Cuprimine, Depen) -- Metal chelator used in treatment of arsenic poisoning. Forms soluble complexes with metals that are subsequently excreted in urine. Adult Dose Arsenic poisoning: 100 mg/kg PO qd; not to exceed 2 g/d divided qid for 5 d Mercury poisoning: 100 mg/kg PO qd divided qid; not to exceed 1 g/d for 3-10 d Pediatric Dose Arsenic poisoning: 100 mg/kg PO qd; not to exceed 1 g/d divided qid for 5 d Mercury poisoning: Administer as in adults Contraindications Documented hypersensitivity; renal insufficiency; previous penicillamine-related aplastic anemia Interactions Increases effects of immunosuppressants, phenylbutazone, and antimalarials; decreases digoxin effects; effects may decrease with coadministration of zinc salts, antacids, and iron Pregnancy D - Unsafe in pregnancy Precautions Thrombocytopenia, agranulocytosis, and aplastic anemia may occur FOLLOW-UP Further Inpatient Care: Arsenic is frequently used for homicidal or suicidal purposes. Thoroughly scrutinize all arsenic toxicity cases for evidence of such activity. Report all cases with possible homicidal association to the proper legal authorities before discharge. Patients with suspected suicidal intent should undergo psychiatric evaluation before discharge from hospital. Further Outpatient Care: Asymptomatic children and adults with elevated lead levels may be candidates for outpatient chelation therapy. Care must be taken to remove the source of heavy metal contamination. Report industrial-related toxicities to OSHA; report childhood cases to the local health department. Complications: Lead toxicity Children are highly sensitive to the toxic effects of lead. Encephalopathy is an indication of poor prognosis, as 85% of patients with encephalopathy develop permanent CNS dysfunction including seizures and mental retardation. Abdominal symptoms are usually resolved after initiation of chelation therapy but may persist for over 15 weeks. Mercury toxicity Complications of mercury toxicity are dose and form dependent. If the toxicity is mild in cases of elemental and mercury salt toxicities, complications are few and recovery is generally good. Residual CNS and neurologic deficits are common in organic mercury toxicities. Arsenic toxicity The complications of arsenic poisoning are largely neurologic. Recovery is often delayed for months. The severity of initial symptoms appears to correlate with the severity of complications and the rate of recovery. Medical/Legal Pitfalls: Failure to diagnose arsenic exposure as a homicidal or suicidal act Failure to report lead toxicity to the local health authorities BIBLIOGRAPHY Section 10 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Ellenhorn MJ: Ellenhorn's Medical Toxicology. 2nd ed. & Wilkins; 1997: 1532-1613. sdorf RG, JB, Fauci AS, et al: on's Principals of Internal Medicine. 12th ed. Vol 2. McGraw-Hill; 1991: 2182-7. Tintinalli JE, Ruiz E, Krome RL: Emergency Medicine: A Comprehensive Study Guide. 4th ed. McGraw-Hill; 1996: 833-41.